0021-972X/07/$15.
00/0
Printed in U.S.A.
APPROACH TO THE PATIENT
Approach to the Patient with Subclinical
Hyperthyroidism
David S. Cooper
Division of Endocrinology, Sinai Hospital of Baltimore, and The Johns Hopkins University School of Medicine, Baltimore,
Maryland 21215
Endogenous subclinical hyperthyroidism, defined by normal circu-
lating levels of free T4 and T3 and low levels of TSH, is a common
clinical entity and is typically caused by the same conditions that
account for the majority of cases of overt hyperthyroidism: Graves’
disease, toxic multinodular goiter, and solitary autonomously func-
tioning thyroid nodules. Subclinical hyperthyroidism has been asso-
ciated with an increased risk of atrial fibrillation and mortality, de-
creased bone mineral density in postmenopausal women, and mild
The Case
A 75-yr-old woman is found to have abnormal thyroid
function tests when screened by her primary care physician,
and she is referred for further evaluation. She has a history
of dyslipidemia and type 2 diabetes. She has no personal or
family history of thyroid disease and no history of neck
irradiation. Her physical examination is generally normal
except for a bilaterally enlarged nodular thyroid gland with
an estimated size of 40 g. Results of thyroid function tests are
as follows: free T4, 1.3 ng/dl (0.8 –1.8); T3, 135 ng/dl (80 –180);
TSH, 0.13 mU/liter (0.5– 4.5). Thyroid sonography reveals a
bilaterally enlarged gland with multiple isoechoic and hy-
perechoic nodules ranging in size from 1 to 3 cm. The nodules
all have a spongiform appearance and a sonolucent halo. A
thyroid radionuclide scan using I123 shows a bilaterally en-
larged gland with multiple areas of increased and decreased
tracer uptake consistent with a multinodular goiter. The 24-h
thyroidal radioiodine uptake is 22%. A bone densitometry
study done 2 yr earlier showed osteopenia in the lumbar
spine and hip.
Background
This elderly woman has subclinical hyperthyroidism, the
mildest form of hyperthyroidism, as defined by the presence
of a low or undetectable serum TSH level in the face of
normal serum free T4 and T3 (or free T3) levels. It was not
identified as a clinical entity until the development of second-
and third-generation TSH assays in the late 1980s, when it
became possible to distinguish low from normal serum TSH
Abbreviations: AF, Atrial fibrillation; LVH, left ventricular hyper-
trophy; RR, relative risk.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the en-
docrine community.
3
The Journal of Clinical Endocrinology & Metabolism 92(1):3–9
Copyright © 2007 by The Endocrine Society
doi: 10.1210/jc.2006-2472
hyperthyroid symptoms. Treatment of subclinical hyperthyroidism
remains controversial, given the lack of prospective randomized con-
trolled trials showing clinical benefit with restoration of the euthyroid
state. Nevertheless, it seems reasonable to treat older individuals
whose serum TSH levels are less than 0.1 mU/liter and certain high-
risk patients, even when the serum TSH is between 0.1 and the lower
limit of the normal range. (J Clin Endocrinol Metab 92: 3–9, 2007)
values. The etiology of subclinical hyperthyroidism can be
divided into two categories: exogenous subclinical hyperthy-
roidism due to the ingestion of intentional or unintentional
suppressive doses of thyroid hormone, and endogenous sub-
clinical hyperthyroidism caused by the usual conditions
leading to thyrotoxicosis, i.e. Graves’ disease, toxic multi-
nodular goiter, autonomously functioning solitary nodules,
and various forms of thyroiditis.
The prevalence of endogenous subclinical hyperthyroid-
ism varies with the TSH cutoff used to define it. For example,
in the NHANES III study, the prevalence was 0.7% using a
cutoff of 0.1 mU/liter and 3.2% using a TSH cutoff of a 0.4
mU/liter (1). The prevalence of subclinical hyperthyroidism
also varies inversely with a population’s iodine intake, being
more common when dietary iodine is relatively deficient (2),
reflecting the higher prevalence of toxic nodules and toxic
multinodular goiter in these populations (3).
Differential Diagnosis of a Low Serum TSH
In addition to bona fide subclinical hyperthyroidism, other
possibilities need to be considered in patients with isolated
serum TSH suppression in other clinical settings: central
hypothyroidism, physiological lowering of serum TSH at the
end of the first trimester of pregnancy, and low serum TSH
levels in the critically ill. In addition, low serum TSH levels
may be seen in apparently healthy elderly people with no
underlying thyroid disease (4, 5). In these elderly people, the
low serum TSH may due to an altered hypothalamic-pitu-
itary-thyroid axis set point that may occur with aging (4).
Clinical Considerations
In approaching this patient to determine the significance
of her thyroid function test abnormalities and whether they
warrant treatment, I would be thinking about three main
4 J Clin Endocrinol Metab, January 2007, 92(1):3–9
issues: These include potential adverse effects on the car-
diovascular system and the skeleton, and the presence or
absence of symptoms or mood disturbance consistent with
thyrotoxicosis. Because subclinical hyperthyroidism is, in
reality, a “mild” form of overt hyperthyroidism, it is rea-
sonable to assume that potential adverse outcomes would be
related to the degree of TSH suppression. Although this may
not always be the case, as discussed below, an expert con-
sensus panel has suggested that patients with serum TSH
levels less than 0.1 mU/liter are at higher risk than those
patients with TSH levels between 0.1 and 0.5 mU/liter (6).
The potential negative effects of subclinical hyperthyroidism
on the cardiovascular system and the skeleton have been the
most thoroughly studied. The presence of hyperthyroid
symptoms and effects on mood and quality-of-life have also
been examined, although in less detail. In the following dis-
cussion, I will review studies of endogenous subclinical hy-
perthyroidism that have investigated these issues, and I will
present what I consider to be key data on the possible benefits
of treatment. Two excellent reviews on the subject of sub-
clinical hyperthyroidism have been published recently (7, 8).
Cardiovascular effects of subclinical hyperthyroidism
The well-known inotropic, chronotropic, and lusitropic
effects of thyroid hormone on the heart and vascular tree (9)
to increase cardiac output and decrease systemic vascular
resistance are also seen to a lesser degree in patients with
subclinical hyperthyroidism. All studies of endogenous sub-
clinical hyperthyroidism have observed an increase in mean
24-h heart rate compared with controls (10 –12). In addition,
one study also noted a statistically significant increase in the
frequency of atrial and ventricular premature beats (10).
Left ventricular hypertrophy (LVH) is a strong predictor
of cardiovascular morbidity and mortality (13). Doppler
echocardiography has shown an increase in left ventricular
mass in patients with subclinical hyperthyroidism (11, 12,
14). One of these reports also suggested that patients with
subclinical hyperthyroidism and hypertension had left ven-
tricular wall thickness that was greater than seen in patients
with hypertension alone (14). However, in a recent large
population-based study involving 1510 individuals, subclin-
ical hyperthyroidism was not associated with LVH, whereas
a positive association with LVH was seen in overt hyper-
thyroidism (15).
Possible deleterious effects of subclinical hyperthyroidism
on systolic and diastolic function have also been examined.
Three studies found minimal or no effect on systolic function
(10, 12, 16), and one showed slightly enhanced systolic func-
tion (11). Biondi et al. (11) also reported a statistically sig-
nificant impairment in diastolic function with decreased
transmitral blood flow due to slowed left ventricular relax-
ation, but significant changes were not observed in two other
studies (10, 12). Although deleterious effects of exogenous
subclinical hyperthyroidism on exercise tolerance have been
found (17, 18), there are no data to address this question in
patients with endogenous subclinical hyperthyroidism.
Because of its obvious clinical importance, an increase in
the frequency of atrial fibrillation (AF) in patients with sub-
clinical hyperthyroidism has attracted a great deal of atten-
Cooper • Approach to the Patient: Subclinical Hyperthyroidism
tion. Tenerz et al. (19) were among the first to report a higher
frequency of AF in endogenous subclinical hyperthyroidism.
This was followed by the report by Sawin et al. (20) of in-
dividuals more than age 60 yr who were prospectively fol-
lowed over a 10-yr period. These authors observed a relative
risk (RR) of 3.1 for AF among individuals with TSH levels less
than 0.1 mU/liter and a RR of 1.6 (95% confidence interval,
1.0 –2.5; P ⬍ 0.04) for those individuals with TSH levels
between 0.1 and 0.4 mU/liter. In a retrospective report on
persons in their mid-60s by Auer et al. (21), AF was seen in
2% of 22,300 euthyroid individuals, 14% of 725 patients with
overt hyperthyroidism, and 13% of 613 patients with endog-
enous subclinical hyperthyroidism (defined as serum TSH ⬍
0.4 mU/liter) (RR for AF: 5.8 and 5.2 for overt and subclinical
hyperthyroidism, respectively). Finally, in a recent report by
Cappola et al. (22), 496 subjects with a mean age of 73 yr with
subclinical hyperthyroidism (serum TSH ⬍ 0.1– 0.44 mU/
liter) and 2639 euthyroid subjects were followed prospec-
tively for a mean of 13 yr. After adjustment for age, sex, and
other risk factors for AF, the RR of subclinical hyperthyroid-
ism for AF was 1.98 (95% confidence interval, 1.29 –3.03).
Furthermore, the risk for AF was similar when only those
subjects with serum TSH levels 0.1– 0.44 mU/liter were in-
cluded in the analysis.
Several other epidemiological studies have examined car-
diovascular risk in patients with subclinical hyperthyroidism
with varying conclusions. In the first, 1191 subjects 60 yr of
age or older with baseline TSH levels measured in 1988 –1989
were followed for 10 yr (23). All-cause and cardiovascular
mortality were greater in subjects with serum TSH levels less
than 0.5 mU/liter at 2, 3, 4, and 5 yr of follow-up. In the
second study, by Gussekloo et al. (24) a cohort of individuals
over age 85 yr was followed for 4 yr. Those with low serum
TSH values had the highest rates of mortality, compared with
both euthyroid and hypothyroid individuals. In contrast,
Walsh et al. (25) followed a younger cohort (mean age 50 yr)
of 2108 subjects and found no increased frequency of coro-
nary artery disease or cardiovascular mortality. The fre-
quency of AF was not specifically examined in any of these
studies. Finally, in their prospective study, Cappola et al. (22)
also found no increase in overall cardiovascular mortality in
subclinically hyperthyroid patients.
Effects of treatment on cardiovascular indices
There are very few studies that have examined the impact
of treatment on cardiovascular abnormalities in patients with
subclinical hyperthyroidism. One early report noted that
cardioversion of AF was unsuccessful in four such patients,
but after normalization of thyroid function with radioiodine
or antithyroid drugs, one patient converted to normal sinus
rhythm spontaneously and the other three responded favor-
ably to cardioversion (26). In another study, six women with
subclinical hyperthyroidism were studied before and after
normalization of serum TSH with methimazole (27). After
treatment, there was an 11% reduction in mean heart rate
(P ⬍ 0.02), a 19% reduction in cardiac output (P ⬍ 0.05), and
a 30% increase in systemic vascular resistance (P ⬍ 0.02).
Finally, in a nonrandomized study in which all patients (me-
dian age 59 yr, n ⫽ 10) were treated with methimazole, there
Cooper • Approach to the Patient: Subclinical Hyperthyroidism
were statistically significant decreases in mean heart rate (82
vs. 74 beats/min, P ⫽ 0.008), the number of atrial (87 vs. 11,
P ⫽ 0.002) and ventricular (8 vs. 0, P ⫽ 0.003) premature
beats/24 h, and left ventricular mass index (90 vs. 71 g/m2)
to values no different from age-matched controls (12).
In my patient with type 2 diabetes, dyslipidemia, and
likely coronary artery disease, I closely questioned her about
possible cardiac rhythm disturbances and other symptoms
(palpitations, angina, dyspnea, etc.), and she had none, and
she had had a normal stress test 3 yr earlier. Although there
are no data that pertain exclusively to subclinically hyper-
thyroid patients who have concomitant cardiovascular dis-
ease, it seems reasonable to assume that the risk for adverse
cardiovascular outcomes would be magnified in persons
who already have cardiac disease.
Skeletal effects of subclinical hyperthyroidism
Overt hyperthyroidism increases bone turnover and is a
well-known risk factor for osteoporosis and fracture (28).
This observation has naturally led to studies of the effects of
subclinical hyperthyroidism on skeletal integrity. Bone min-
eral density is lower at all sites in postmenopausal women,
especially in sites that are predominantly cortical bone (29,
30). In contrast, the bone density in premenopausal women
with subclinical hyperthyroidism appears to be normal (31),
although bone turnover markers, including bone alkaline
phosphatase, urinary pyridinoline, and urinary deoxypyr-
idinoline were elevated in a group of premenopausal women
with subclinical hyperthyroidism whose TSH levels were 0.4
mU/liter or less, compared with antithyroid drug-treated
women whose TSH levels were maintained within the nor-
mal range (32).
Only a few studies have examined the risk of fractures in
patients with subclinical hyperthyroidism, and none of them
have exclusively studied a cohort of women with endoge-
nous subclinical hyperthyroidism. In one report that exam-
ined a cohort of women 65 yr of age or older, the risk of
vertebral fracture was elevated 4-fold and hip fracture was
elevated 3-fold in patients with serum TSH values 0.1 mU/
liter or less compared with women with normal serum TSH
levels (33). Women with TSH values between 0.1 and 0.5
mU/liter had no increased risk of fracture. However, this
study did not distinguish between women with exogenous
and endogenous subclinical hyperthyroidism. Furthermore,
because serum free T4 and T3 values were not reported, it is
possible that some of the women in the cohort may actually
have had overt hyperthyroidism rather than subclinical
hyperthyroidism.
Effects of therapy on bone metabolism
Perhaps the strongest evidence for an effect of endogenous
subclinical hyperthyroidism on bone mineral density comes
from intervention trials, although none have been random-
ized or placebo-controlled. In one small study, postmeno-
pausal women with subclinical hyperthyroidism were fol-
lowed prospectively for 2 yr, with one group (n ⫽ 8)
receiving methimazole to normalize thyroid function and the
other group (n ⫽ 8) remaining untreated (34). At the end of
the follow-up period, distal forearm bone mineral density
J Clin Endocrinol Metab, January 2007, 92(1):3–9 5
was stable and significantly higher in the treatment group
compared with the untreated group. In the second study,
postmenopausal women with multinodular goiter and sub-
clinical hyperthyroidism were given radioactive iodine if
they had compressive symptoms (n ⫽ 16), or remained un-
treated if asymptomatic (n ⫽ 12) (35). At the end of the 2-yr
follow-up period, bone mineral density remained stable in
the spine in the treatment group and continued to fall in the
untreated group. Similarly, bone mineral density in the hip
increased significantly after 2 yr in the treatment group but
fell in the untreated group. In a small randomized study of
premenopausal women, bone mineral density at baseline
was slightly but not significantly different from age-matched
controls and did not improve after 6 months of euthyroidism
(36).
Based on these clinical studies, I would be concerned about
further bone loss in my patient who already had osteopenia
on a dual-energy x-ray absorptiometry study done 2 yr ear-
lier, and it would be reasonable to repeat this study now that
subclinical hyperthyroidism has been detected.
Symptoms and quality of life in subclinical
hyperthyroidism
There are few studies that have examined the possibility
that endogenous subclinical hyperthyroidism could cause
mild hyperthyroid symptoms or affect quality of life. One
of the earliest studies compared 20 patients with overt
hyperthyroidism, 20 with “pre-clinical hyperthyroidism”
(with normal serum T3 and T4 but suppressed TSH re-
sponses to TRH), and 20 euthyroid controls (37). Subjects
with subclinical hyperthyroidism had increased anxiety,
irritability, and decreased attentiveness and concentra-
tion. Furthermore, they also had the same prevalence of
hyperthyroid symptoms as patients with overt hyperthy-
roidism using the Crooks’ index of hyperthyroidism. In a
group of elderly individuals with subclinical hyperthy-
roidism (serum TSH ⬍ 0.1 mU/liter) reported by Stott et
al. (38), an increase in hyperthyroid symptoms were not
seen, but these individuals had a higher score on the
Wayne index, a clinical index of hyperthyroidism. In an-
other study (39), patients with subclinical hyperthyroid-
ism (serum TSH ⱕ 0.2 mU/liter) had a frequency of hy-
perthyroid symptoms that was intermediate between
normal controls and patients with overt hyperthyroidism.
The ability to concentrate and short-term memory were
normal in all groups. The same researchers paradoxically
found that individuals with subclinical hyperthyroidism
had an increased frequency of palpitations but had normal
mood, sleep quality, and psychometric testing (40). More
recently, two other studies also described an increase in
typical hyperthyroid symptoms (palpitations, tremor, heat
sensitivity, sweating, nervousness) in young and middle-
aged patients with endogenous subclinical hyperthyroid-
ism (11, 12). Using the Short Form-36 (SF-36) health ques-
tionnaire, Biondi et al. (11) also observed a statistically
significant reduction in both the mental and physical com-
ponent scores in patients with subclinical hyperthyroid-
ism (mean serum TSH, 0.15 mU/liter). The reductions in
quality of life were proportional to the degree of hyper-
6 J Clin Endocrinol Metab, January 2007, 92(1):3–9
thyroid symptoms experienced by the group using a val-
idated symptom rating scale. On the other hand, in a
community-based sample of 127 persons aged 65 yr and
older with subclinical hyperthyroidism, there were no sig-
nificant differences in mood, anxiety, or cognition between
subclinically hyperthyroid persons and those who were
euthyroid (41).
Effects of the therapy on symptoms and quality of life
Only one study has examined the effect of treatment on
hyperthyroid symptoms in patients with endogenous sub-
clinical hyperthyroidism, and none have examined quality of
life or mood. Using a nonrandomized study design, Sgarbi
et al. (12) investigated 10 patients with subclinical hyperthy-
roidism (mean serum TSH, 0.05 mU/liter) before and 6
months after restoration of a euthyroid state with methim-
azole. The Wayne index, a validated hyperthyroid symptom
instrument, declined from a mean of 12 points to a mean of
2 points, which was a highly significant change, and close to
the score seen in a healthy control group.
To assess the potential impact of subclinical hyperthyroid-
ism on my patient, I inquired about typical hyperthyroid
symptoms, but there were none. I also inquired about
changes in mood (especially anxiety) and possible alterations
in cognitive function. However, most current data do not
support an association between these problems and subclin-
ical hyperthyroidism, at least in older patients.
Other metabolic effects of subclinical hyperthyroidism
A recent study of 13 patients with subclinical hyperthy-
roidism (mean age, 58 yr; mean TSH, 0.14 mU/liter) showed
an increased basal oxygen consumption compared with age-
matched controls that decreased to normal (210 vs. 142 ml O2
/min䡠m2) after treatment with methimazole (42). In another
study, patients with subclinical hyperthyroidism (n ⫽ 24;
mean age, 53 yr; serum TSH, 0.005– 0.02 mU/liter) were
found to have decreased muscle strength compared with
controls, as well as decreased midthigh cross-sectional area
compared with controls, both of which normalized 6 –9
months after treatment with radioiodine or surgery (43).
My patient did not have dyspnea on exertion, symptoms
suggesting a decrease in exercise tolerance, or muscle weak-
ness. No formal studies were performed to assess for these
possibilities.
TABLE 1. Review of guidelines promulgated by various professional groups
Organization
American Thyroid Association (ATA) (48)
American Association of Clinical
Endocrinologists (AACE) (49)
Royal College of Physicians (50)
American College of Physicians (51)
ATA, AACE, Endocrine Society Consensus
Conference (6)
SH, Subclinical hyperthyroidism.
a
Category B: Recommend. The recommendation is based on fair evidence that the service or intervention can improve important health
outcomes.
b
Category E: Recommend against. The recommendation is based on fair evidence that the service or intervention does not improve important
health outcomes or that harms outweigh benefits.
Cooper • Approach to the Patient: Subclinical Hyperthyroidism
The risk of progression to overt hyperthyroidism
Patients with subclinical hyperthyroidism are at risk for
progressing to overt hyperthyroidism, but the natural his-
tory is poorly defined. In patients with detectable serum TSH
values, subclinical hyperthyroidism may frequently resolve
spontaneously. For example, Parle et al. (44) observed, in a
cohort of patients with subclinical hyperthyroidism followed
for 12 months, that serum TSH values reverted to normal in
38 of 50 patients with serum TSH values between 0.05 and
0.5 mU/liter but remained undetectable in 14 of 16 patients
with baseline TSH less than 0.05 mU/liter. With regard to
progression to overt hyperthyroidism, Sawin et al. (45) re-
ported a 4.1% rate of progression to overt hyperthyroidism
over 4 yr among a group of elderly individuals with serum
TSH levels less than 0.1 mU/liter. Stott et al. (38) reported
over a mean of 7 months (range, 4 –12 months) of follow-up
that seven of 15 patients reverted to TSH levels greater than
0.2 mU/liter, whereas four of 15 developed overt hyperthy-
roidism. A somewhat lower rate of progression was ob-
served by Parle et al. (23), who observed a rate of approxi-
mately 4% (three of 70 people) over a 10-yr follow-up period.
The etiology of subclinical hyperthyroidism may play a role
in determining whether subclinical hyperthyroidism re-
solves or progresses. For example, Woeber (46) observed that
serum TSH values normalized in five of seven patients with
Graves’ disease and subclinical hyperthyroidism (baseline
TSH ⬍ 0.03– 0.06 mU/liter) followed for 3–19 months,
whereas it remained subnormal (baseline TSH 0.1– 0.29 mU/
liter) in patients with multinodular goiters followed for 11–36
months.
Treatment Considerations
A review of guidelines promulgated by various profes-
sional groups shows a uniform uncertainty about the ap-
propriate management of subclinical hyperthyroidism (Ta-
ble 1). In 2005, an expert panel composed of members of the
American Thyroid Association, The Endocrine Society, and
The American Association of Clinical Endocrinologists pro-
duced, for the first time, evidence-based recommendations
for treatment of subclinical hyperthyroidism (6). The panel
concluded, based on “fair evidence,” that treatment should
be offered to “elderly” individuals and those with other risk
factors (especially cardiac disease and osteoporosis), whose
Guideline
No opinion
Periodic assessment to determine individual therapeutic
options
No agreement on benefits of detecting/treating SH
No agreement on benefits of detecting/treating SH
Treat older individuals or patients with risks (cardiac,
postmenopausal if TSH ⬍ 0.1 (Category B)a (Category E
for TSH ⬎ 0.1)b
Cooper • Approach to the Patient: Subclinical Hyperthyroidism J Clin Endocrinol Metab, January 2007, 92(1):3–9 7

serum TSH levels are less than 0.1 mU/liter. The panel also
concluded that the evidence was insufficient to recommend
therapy for patients with serum TSH greater than 0.1– 0.45
mU/liter. Interestingly, these recommendations are only
partly consistent with the results of a survey of members of
the American Thyroid Association (47) conducted in 2002.
Given hypothetical cases of subclinical hyperthyroidism, re-
spondents were more likely to recommend therapy in pa-
tients with undetectable (⬍0.01 mU/liter) vs. more mildly sup-
pressed serum TSH values (0.2 mU/liter) and were more likely
to recommend treating older vs. younger patients. However,
only 66% of respondents would have recommended therapy in
an older osteopenic female patient with a serum TSH less than
0.01 mU/liter. Furthermore, 13% would have recommended
treatment in a 28-yr-old patient with a serum TSH value of
0.1– 0.5 mU/liter.
Controversies and Unanswered Questions
Uncertainty about the proper management of subclinical
hyperthyroidism will remain as long as there are no ran-
domized prospective trials. However, there is a consensus
that therapy is reasonable and appropriate in elderly indi-
viduals and in persons with heart disease or evidence of bone
loss who have serum TSH levels less than 0.1 mU/liter. On
the other hand, the proper management of similarly at-risk
patients with serum TSH levels greater than 0.l but less than
0.4 is an unanswered question. Although some epidemio-
logical evidence suggests that the risks of death and AF are
similar to those in patients with serum TSH less than 0.1
mU/liter, few clinical studies have examined the effects of
subclinical hyperthyroidism on the heart, skeleton, or symp-
toms in patients with serum TSH levels that are subnormal
but greater than 0.1 mU/liter. A second unresolved issue is
the appropriate management of premenopausal women and
younger men with subclinical hyperthyroidism. The only
data showing adverse consequences in these groups are from
the one study showing an increase in bone turnover markers
in premenopausal women (32) and the few studies showing
an increase in myocardial structure or heart rate (11, 12) or
symptoms (11, 12) that have included middle-aged patients.
Finally, there are healthy elderly persons whose serum TSH
levels are less than 0.1 mU/liter who have serum free T4 and
T3 levels that are in the lower half of the normal range and
have no evidence of thyroid or pituitary disease (4). Whether
such persons have an altered set point of the pituitary thyroid
axis, subtle thyroid dysfunction, or unrecognized nonthy-
roidal illness is uncertain. But, it is difficult to believe that
they are at the same risk for adverse cardiac or skeletal
outcomes as persons with thyroid hormone levels that are in
the upper part of the normal range. Yet, with recommenda-
tions targeted to the serum TSH level alone, therapy is
deemed advisable, but may be unnecessary. Figure 1 is an
algorithm that outlines a proposed plan for the evaluation
and therapy of subclinical hyperthyroidism.

Serum TSH
persistently subnormal;
normal
FT4 and T3 or FT3

Postmenopausal or > Premenopausal or

age 60 yr, or history of < age 60 yr, no history
heart disease, of heart disease,
osteoporosis, or osteoporosis or
symptoms symptoms

TSH <0.1 mU/l TSH 0.1-0.4 mU/l TSH <0.1 mU/ll TSH 0.1-0.4 mU/ l

Radioiodine Consider radioiodine Radioiodine Consider

uptake and scan; uptake and scan; uptake and scan; radioiodine
bone density bone density study bone density study uptake and scan
study (women) (women) (women)

Therapy No therapy
Therapy* with Consider therapy**
optional****
radioiodine with radioiodine
or thionamides*** or thionamides***

FIG. 1. An algorithm that outlines a proposed plan for the evaluation and therapy of subclinical hyperthyroidism. *, Based on data showing
higher mortality (23, 24), atrial fibrillation (20 –22), bone loss (29 –31), symptoms or reduced quality of life (11, 12) in some studies. **, Based
on higher mortality (23, 24) and atrial fibrillation (22) in some studies. ***, Radioiodine preferred in patients with toxic multinodular goiter
or solitary autonomous nodules. ****, Little evidence of clinically significant benefit in younger asymptomatic individuals without heart disease
or bone loss.
8 J Clin Endocrinol Metab, January 2007, 92(1):3–9
Returning to the Patient
The patient was elderly, had coexisting cardiovascular risk
factors, and had a serum TSH that was near (0.13 mU/liter)
the threshold at which the Consensus Panel recommends
therapy (⬍0.1 mU/liter). Therefore, therapy with radioio-
dine was offered to the patient. Radioiodine was chosen
rather than antithyroid drugs because multinodular goiter
was the cause of her subclinical hyperthyroidism. Had
Graves’ disease been the etiology, a 12- to 18-month course
of antithyroid drugs would also have been reasonable. After
discussing the potential risks of worsening hyperthyroidism
and postablative hypothyroidism, and the theoretical bene-
fits of a decreased risk of AF and stabilization or improve-
ment in bone mineral density, she received a dose of 30 mCi
131I. The dose was roughly calculated based on an estimated
gland size of 40 g, a desired treatment dose of 150 ␮Ci/g of
thyroid tissue, and the 24-h radioiodine uptake of 22%. Un-
like the case in overt hyperthyroidism, there are currently no
recommendations to pretreat elderly patients with subclin-
ical hyperthyroidism with antithyroid drugs to normalize
thyroid function before radioiodine administration. Accord-
ingly, she did not receive antithyroid drugs first, and al-
though thyroid function was not monitored sooner than 6 wk
after therapy, there were no acute clinical adverse effects (i.e.
worsening hyperthyroid symptoms, AF, etc.). Thyroid func-
tion was unchanged at 6 wk, but 3 months later her serum
TSH had risen to 0.25 mU/liter, and after 6 months it rose to
0.3 mU/liter, with a decline in serum free T4 to 1.0 ng/dl.
Thyroid function has remained normal over 18 months of
follow-up. A repeat bone density determination done 6
months after radioiodine therapy was unchanged compared
with the prior study done 2 yr earlier.
Conclusions
Endogenous subclinical hyperthyroidism is a frequent
medical problem and may cause several adverse outcomes,
especially in the elderly. Although treatment guidelines have
been proposed, it remains uncertain whether treatment pre-
vents subsequent cardiovascular morbidity or mortality.
Only randomized prospective trials will be able to provide
the answer to this important clinical problem. Future trials
should also include younger patients, as well as older pa-
tients with serum TSH values between 0.1 and 0.4 mU/liter.
Acknowledgments
Received November 10, 2006. Accepted November 13, 2006.
Address all correspondence and requests for reprints to: David S.
Cooper, M.D., Division of Endocrinology, Sinai Hospital of Baltimore,
2435 West Belvedere Avenue, Hoffberger Building, Suite 56, Baltimore,
Maryland 21215. E-mail dcooper@lifebridgehealth.org.
The author has nothing to declare.
References
1. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spen-
cer CA, Braverman LE 2002 Serum TSH, T4, and thyroid antibodies in the
United States population (1988 to 1994): National Health and Nutrition Ex-
amination Survey (NHANES III). J Clin Endocrinol Metab 87:489 – 499
2. Laurberg P, Pedersen KM, Hreidarsson A, Sigfusson N, Iversen E, Knudsen
PR 1998 Iodine intake and the pattern of thyroid disorders: a comparative
epidemiological study of thyroid abnormalities in the elderly in Iceland and
in Jutland, Denmark. J Clin Endocrinol Metab 83:765–769
Cooper • Approach to the Patient: Subclinical Hyperthyroidism
3. Belfiore A, Sava L, Runello F, Tomaselli L, Vigneri R 1996 Solitary auton-
omously functioning thyroid nodules and iodine deficiency. J Clin Endocrinol
Metab 56:283–287
4. Lewis GF, Alessi CA, Imperial JG, Refetoff S 1991 Low serum free thyroxine
index in ambulating elderly is due to a resetting of the threshold of thyrotropin
feedback suppression. J Clin Endocrinol Metab 73:843– 849
5. Mariotti S, Barbesino G, Caturegli P, Bartalena L, Sansoni P, Fagnoni F,
Monti D, Fagiolo U, Franceschi C, Pinchera A 1993 Complex alteration of
thyroid function in healthy centenarians J Clin Endocrinol Metab 77:1130 –1134
6. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA,
Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman
NJ 2004 Subclinical thyroid disease: scientific review and guidelines for di-
agnosis and management. JAMA 291:228 –238
7. Biondi B, Palmieri EA, Klain M, Schlumberger M, Filetti S, Lombardi G 2005
Subclinical hyperthyroidism: clinical features and treatment options. Eur J
Endocrinol 152:1–9
8. Papi G, Pearce EN, Braverman LE, Betterle C, Roti E 2005 A clinical and
therapeutic approach to thyrotoxicosis with thyroid-stimulating hormone sup-
pression only. Am J Med 118:349 –361
9. Klein I, Ojamaa K 2001 Thyroid hormone and the cardiovascular system.
N Engl J Med 344:501–509
10. Petretta M, Bonaduce D, Spinelli L, Vicario MLE, Nuzzo V, Marciano F,
Camuso P, De Sanctis V, Lupoli G 2001 Cardiovascular haemodynamics and
cardiac autonomic control in patients with subclinical and overt hyperthy-
roidism. Eur J Endocrinol 145:691– 696
11. Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Saccà L, Filetti S,
Lombardi G, Perticone F 2000 Endogenous subclinical hyperthyroidism af-
fects quality of life and cardiac morphology and function in young and middle-
aged patients. J Clin Endocrinol Metab 85:4701– 4705
12. Sgarbi JA, Villaca F, Garbeline B, Villar HE, Romaldini JH 2003 The effects
of early antithyroid therapy for endogenous subclinical hyperthyroidism on
clinical and heart abnormalities. J Clin Endocrinol Metab 88:1672–1677
13. Kannel WB, Cobb J 1992 Left ventricular hypertrophy and mortality–results
from the Framingham Study. Cardiology 81:291–298
14. Tamer I, Sargin M, Sargin H, Seker M, Babalik E, Tekce M, Yayla A 2005 The
evaluation of left ventricular hypertrophy in hypertensive patients with sub-
clinical hyperthyroidism. Endocr J 52:421– 425
15. Dorr M, Wolff B, Robinson DM, John U, Ludemann J, Meng W, Felix SB,
Volzke H 2005 The association of thyroid function with cardiac mass and left
ventricular hypertrophy. J Clin Endocrinol Metab 90:673– 677
16. Yavuz H, Altunbas H, Balci MK, Demircioǧlu F, Çakir M, Karayalçin Ü 2000
Normal systolic time intervals in subclinical hyperthyroidism. J Endocrinol
Invest 23:38 (Abstract)
17. Biondi B, Fazio S, Cuocolo A, Sabatini D, Nicolai E, Lombardi G, Salvatore
M, Sacca L 1996 Impaired cardiac reserve and exercise capacity in patients
receiving long-term thyrotropin suppressive therapy with levothyroxine.
J Clin Endocrinol Metab 81:4224 – 4228
18. Mercuro G, Panzuto MG, Bina A, Leo M, Cabula R, Petrini L, Pigliaru F,
Mariotti S 2000 Cardiac function, physical exercise capacity, and quality of life
during long-term thyrotropin-suppressive therapy with levothyroxine: effect
of individual dose tailoring. J Clin Endocrinol Metab 85:159 –164
19. Tenerz A, Forberg R, Jansson R 1990 Is a more active attitude warranted in
patients with subclinical thyrotoxicosis? J Intern Med 228:229 –233
20. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, Wilson PW,
Benjamin EJ, D’Agostino RB 1994 Low serum thyrotropin concentrations as
a risk factor for atrial fibrillation in older persons. N Engl J Med 331:1249 –1252
21. Auer JA, Scheibner P, Mische T, Langsteger W, Eber O, Eber B 2001 Sub-
clinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J
142:838 – 842
22. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, Tracy
RP, Ladenson PW 2006 Thyroid status, cardiovascular risk, and mortality in
older adults. JAMA 295:1033–1041
23. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA 2001 Predic-
tion of all-cause and cardiovascular mortality in elderly people from one low
serum thyrotropin result: a 10-year cohort study. Lancet 358:861– 865
24. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp
RG 2004 Thyroid status, disability and cognitive function, and survival in old
age. JAMA 292:2591–2599
25. Walsh JP, Bremner AP, Bulsara MK, O’Leary P, Leedman PJ, Feddema P,
Michelangeli V 2005 Subclinical thyroid dysfunction as a risk factor for car-
diovascular disease. Arch Intern Med 165:2467–2472
26. Forfar JC, Feek CM, Miller HC, Toft AD 1981 Atrial fibrillation and isolated
suppression of the pituitary-thyroid axis: response to specific antithyroid ther-
apy. Int J Cardiol 1:43– 48
27. Faber J, Wiinberg N, Schifter S, Mehlsen J 2001 Hemodynamic changes
following treatment of subclinical and overt hyperthyroidism. Eur J Endocri-
nol 145:391–396
28. Vestergaard P, Rejnmark L, Weeke J, Mosekilde L 2000 Fracture risk in
patients treated for hyperthyroidism. Thyroid 10:341–348
29. Foldes J, Tarjan G, Szathmary M, Varga F, Krasznai I, Horvath C 1993 Bone
mineral density in patients with endogenous subclinical hyperthyroidism: is
Cooper • Approach to the Patient: Subclinical Hyperthyroidism
the thyroid status a risk factor for osteoporosis? Clin Endocrinol (Oxf) 39:
521–527
30. Mudde AH, Reijnders FJ, Kruseman AC 1992 Peripheral bone density in
women with untreated multinodular goitre. Clin Endocrinol (Oxf) 37:35–39
31. Gurlek A, Gedik O 1999 Effect of endogenous subclinical hyperthyroidism on
bone metabolism and bone mineral density in premenopausal women. Thy-
roid 9:539 –543
32. Kumeda Y, Inaba M, Tahara H, Kurioka Y, Ishikawa T, Morii H, Nishizawa
Y 2000 Persistent increase in bone turnover in Graves’ patients with subclinical
hyperthyroidism. J Clin Endocrinol Metab 85:4157– 4161
33. Bauer DC, Ettinger B, Nevitt MC, Stone KL 2001 Risk for the study of
osteoporotic fractures. Risk for fracture in women with low serum levels of
thyroid-stimulating hormone. Ann Intern Med 134:561–568
34. Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC 1994 Bone metab-
olism during anti-thyroid drug treatment of endogenous subclinical hyper-
thyroidism. Clin Endocrinol (Oxf) 41:421– 424
35. Faber J, Jensen IW, Petersen L, Nygaard B, Hegedus L, Siersbaek-Nielsen K
1998 Normalization of serum thyrotropin by mean of radioiodine treatment in
subclinical hyperthyroidism. Effect of bone loss in postmenopausal women.
Clin Endocrinol (Oxf) 48:285–290
36. Yonem O, Dokmetas HS, Aslan SM, Erselcan T 2002 Is antithyroid treatment
really relevant for young patients with subclinical hyperthyroidism? Endocr
J 49:307–314
37. Rockel M, Teuber J, Schmidt R, Kaumeier S, Hafner H, Usadel KH 1987
[Correlation of “latent hyperthyroidism” with psychological and somatic
changes.] Klin Wochenschr 65:264 –273
38. Stott DJ, McLellan AR, Finlayson J, Chu P, Alexander WD 1991 Elderly
patients with suppressed serum TSH but normal free thyroid hormone levels
usually have mild thyroid overactivity and are at increased risk of developing
overt hyperthyroidism. Q J Med 78:77– 84
39. Schlote B, Nowotny B, Schaaf L, Kleinbohl D, Schmidt R, Teuber J, Paschke
R, Vardarli I, Kaumeier S, Usadel KH 1992 Subclinical hyperthyroidism:
physical and mental state of patients. Eur Arch Psychiatry Clin Neurosci
241:357–364
40. Schlote B, Schaaf L, Schmidt, R Pohl T, Vardarli I, Schiebeler H, Zober MA,
JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.
J Clin Endocrinol Metab, January 2007, 92(1):3–9 9
Usadel KH 1992 Mental and physical state in subclinical hyperthyroidism:
investigations in a normal working populations. Biol Psych 32:48 –56
41. Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, Parle JV
2006 Is subclinical thyroid dysfunction in the elderly associated with depres-
sion or cognitive dysfunction? Ann Intern Med 145:573–581
42. Kvetny J 2005 Subclinical hyperthyroidism in patients with nodular goiter
represents a hypermetabolic state. Exp Clin Endocrinol Diabetes 113:122–126
43. Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS 2006 The
impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid
16:375–380
44. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC 1991 Prevalence
and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly
in the United Kingdom. Clin Endocrinol (Oxf) 34:77– 83
45. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM
1991 Low serum thyrotropin (thyroid-stimulating hormone) in older persons
without hyperthyroidism. Arch Intern Med 151:165–168
46. Woeber KA 2005 Observations concerning the natural history of subclinical
hyperthyroidism. Thyroid 15:687– 691
47. McDermott MT, Woodmansee WW, Haugen BR, Smart A, Ridgway EC 2003
The management of subclinical hyperthyroidism by thyroid specialists. Thy-
roid 13:1133–1139
48. Singer PA, Cooper DS, Levy EG, Ladenson PW, Braverman LE, Daniels G,
Greenspan FS, McDougall IR, Nikolai TF 1995 Treatment guidelines for
patients with hyperthyroidism and hypothyroidism. Standards of Care Com-
mittee, American Thyroid Association. JAMA 273:808 – 812
49. American Association of Clinical Endocrinologists 2002 American Associa-
tion of Clinical Endocrinologists medical guidelines for clinical practice for the
evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr
Pract 8:457– 469
50. Vanderpump MP, Ahlquist JA, Franklyn JA, Clayton RN 1996 Consensus
statement for good practice and audit measures in the management of hypo-
thyroidism and hyperthyroidism. BMJ 313:539 –544
51. American College of Physicians 1998 Screening for thyroid disease. Ann
Intern Med 129:141–143